Author ResponseDear Dr. Papageorghiou, We welcome the letter from Garabedian et al. 1and their interest in our updated systematic review, comparing admission cardiotocography (CTG) and intermittent auscultation (IA) in low- risk term pregnancies2. While we focused on updating the meta-analysis, we agree that the results apply only to the settings and populations included in the original randomised controlled trials (RCTs). Clear limitations and challenges in interpreting the RCTs’ findings (discussed in Section 4.3,Research and Policy Implications 2) arise from methodological differences and poorly defined concepts, limiting the strength of the conclusions. Future work should ensure objective, consistent and reproducible definitions of the:target population;timing of CTG/IA administration;precise protocols for IA administration and admission CTG (including timing and duration);criteria for abnormal trace, directly linked to (6) and (7) below;clinical management guidelines for those with abnormal findings;precise study outcomes, based on the question/s the test is seeking to answer.Considering that classic two-arm RCTs are challenging to conduct for rare heterogeneous pregnancy outcomes (e.g. hypoxic-ischaemic enteropathy or perinatal mortality), routinely collected large datasets and/or innovative trial designs may play an important role in generating reliable evidence. We also agree that, the particular question “Is this fetus fit to undertake the journey of labour? ”3 is fundamental and future research could evaluate the utility of admission CTG and IA specifically for this. Moreover, the absence of accelerations and cyclicity may play a major role at admission, while current intrapartum CTG and IA protocols are typically focused on baseline and decelerations. This discrepancy drives the need for different interpretation criteria for admission CTG. In prior work, we analysed the data of 27,000 births4 and showed that the CTGs recorded within the first hour of admission were more likely to have baseline fetal heart rate ≥150bpm; non-reactive trace; reduced variability and decelerative capacity; and no accelerations4 in babies later born with severe complications (perinatal death, seizures, neonatal encephalopathy or need for intensive resuscitation). Given the complexity of labour and the nature of acute intrapartum events, a CTG at labour onset cannot foretell all causes of severe compromise at birth. However, identifying those with abnormal admission CTG is of particular interest because it provides an opportunity to prevent further deterioration, rather than discover compromise many hours later after the additional hypoxic stress of labour. Finally, the appropriate clinical response to an abnormal admission CTG findings, amongst other things, is determined by labour progression, parity, maternal and pregnancy-specific risk factors, patient preferences, and the clinical resources available within the unit. The meta-analysis indicated that concerns about increased caesarean deliveries are likely overstated2 and we believe that objective, evidence-based criteria to define abnormal admission CTG and clinical protocols could minimise false-positive findings and safely reduce unnecessary interventions. Given the inherent uncertainty and imprecision of current assessment tools, it is crucial to conceptualise risk as a continuum and to engage patients in informed, shared decision-making that carefully balances potential risks and benefits in light of the best available evidence. Yours sincerely, Mariana Tomé, Aimée A. K. Lovers, Lawrence Impey, Jane E. Hirst, Antoniya Georgieva Oxford Labour Monitoring Nuffield Department of Women’s & Reproductive Health University of Oxford, Oxford, United Kingdom

Objective To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam. Design Case-cohort study Setting Tu Du Hospital, Ho Chi Minh City, Viet Nam Population Women with a viable singleton pregnancy (n=5000). Methods Maternal serum was collected between 19 +0-22 +6 weeks’ gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks were tested, with model tuning using clinical factors. Main outcomes measures All PTBs (any birth ≤37 weeks’ gestation) and spontaneous PTBs (birth ≤37 weeks’ gestation with clinical signs of initiation of parturition). Results Complete data were available for 4984 (99.7%), cohort PTB rate=6.7%; n=335. We observed an inverse association between IGFBP4/SHBG ratio and gestational age at birth (p=0.017); AUC 0.60 (95% CI, 0.53-0.68). Including previous PTB (multiparous women) or prior miscarriage (primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks’ gestation). Optimal performance (AUC 0.74) was between 19-20 weeks’ gestation, for BMI >21kg/m 2 and age 20-35 years. Conclusions We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.

Exposure to extreme heat in pregnancy increases the risk of stillbirth. Progress in reducing stillbirth rates has stalled, and populations are increasingly exposed to high temperatures and climate events that may further undermine health strategies. This narrative review summaries the current clinical and epidemiological evidence of the impact of maternal heat exposure on stillbirth risk. 19 out of 20 studies found an association between heat and stillbirth risk. Recent studies based in low- middle- income countries and tropical settings add to the existing literature to demonstrate that all populations are at risk. Additionally, both short-term heat exposure and whole-pregnancy heat exposure increase the risk of stillbirth. A definitive threshold of effect has not been identified, as most studies define exposure as > 90 th percentile of the usual temperature for that population. Therefore, the association between heat and stillbirth has been found with exposures from as low as >12.64°C up to >46.4°C. The pathophysiological pathways by which maternal heat exposure may lead to stillbirth, based on human and animal studies, include both placental and embryonic or fetal impacts. Although evidence gaps remain and further research is needed to characterise these mechanistic pathways in more detail, preliminary evidence suggests epigenetic changes, alteration in imprinted genes, congenital abnormalities, reduction in placental blood flow, size and function all play a part. Finally, we explore this topic from a public health perspective; we discuss and evaluate the current public health guidance on minimising the risk of extreme heat in the community. There is limited pregnancy specific guidance within heatwave planning, and no evidence-based interventions have been established to prevent poor pregnancy outcomes. We highlight priority research questions to move forward in the field and specifically note the urgent need for evidence-based interventions that are sustainable.